Our laboratory is interested in the mechanisms by which nascent secretory and membrane proteins are translocated across or integrated into the endoplasmic reticulum membrane, appropriately modified, folded, and assembled prior to subsequent transit to various parts of the cell. One largely unexplored concept is the idea that certain aspects of translocation can be regulated, or misregulated in the pathogenesis of disease. This notion has been difficult to explore in the absence of a mechanistic understanding of the basic processes involved. With the recent insights into simple secretory protein translocation, the stage is now set to ask whether more complex substrates can be subject to regulation in some aspect of their biogenesis. Thus, the long term objectives of our laboratory are to reveal the biogenesis of secretory and membrane proteins as a novel site of regulation in the cell, identify the regulatory mechanisms and factors involved, and define roles for this type of regulation in cell biology and disease pathogenesis. We are taking two approaches to achieving these objectives. First, we are using an in vitro biochemical system to reconstitute and study key steps in the biogenesis of medically relevant secretory and membrane proteins. Steps that are particularly sensitive to perturbation or are determined to be altered for disease-associated mutants are dissected further. Insights and tools gained from these biochemical studies are used to develop specific testable hypotheses on the pathophysiology of diseases associated with the substrates under study. These hypotheses are tested using in vivo model systems including cultured cells and transgenic mice. At present, proteins under study in the laboratory include the prion protein and angiotensinogen, which are involved in neurodegenerative disease and hypertension, respectively. It is envisioned that the insights from these model substrates will reveal a richly complex point of regulation that has direct implications for physiology and disease.